The research and development of antitumor agents has been actively pursued. A variety of effective antitumor agents are clinically used in the treatment of malignant tumors.
For example, tegafur is a drug that is activated in vivo and releases an active form, i.e., 5-fluorouracil (hereinafter referred to as “5-FU”), and is known as an improved antitumor agent that exhibits less toxicity and side effects than 5-FU itself. Moreover, a combined drug of tegafur and uracil is known to have a greater antitumor effect than tegafur alone. In particular, a combined drug having a tegafur to uracil molar ratio of 1 to 4 is commercially available as capsules and granules (trade name: UFT, manufactured by Taiho Pharmaceutical Co., Ltd.). This combined drug exhibits significantly enhanced antitumor effect compared with tegafur alone due to the fact that uracil, which does not have any antitumor effect by itself, inhibits the inactivation of 5-FU which is promptly metabolized and inactivated in vivo.
Japanese Patent Publication No. 2557303 discloses that the antitumor effect of an antitumor agent containing a combined drug of tegafur and uracil can be markedly potentiated without an increase in toxicity when it is used in combination with folinic acid or a salt thereof.
WO90/07334 discloses that the use of oxonic acid or a salt thereof in combination with 5-FU or a 5-FU derivative can inhibit the development of inflammation that may be caused by 5-FU or the 5-FU derivative.
Japanese Patent Publication No. 2614164 discloses an antitumor effect potentiator containing as active ingredients 2,4-dihydroxy-5-chloropyridine (gimeracil) and oxonic acid or a salt thereof which can increase the antitumor effect of tegafur while inhibiting side effects. It also discloses a 3-membered antitumor agent containing tegafur, gimeracil, and oxonic acid or a salt thereof as active ingredients. In particular, a combined drug containing tegafur, gimeracil, and oteracil potassium in a molar ratio of 1:0.4:1 is commercially available as capsules (trade name: TS-1, manufactured by Taiho Pharmaceutical Co., Ltd.). This antitumor agent has an enhanced antitumor effect due to the function of gimeracil, which exhibits a 5-FU degradation inhibitory effect about 200 times greater than that of uracil. Moreover, oxonic acid and salts thereof specifically inhibit the increase in gastrointestinal toxicity that is likely to be accompanied by the antitumor effect potentiation when tegafur and gimeracil are used in combination, thereby enhancing the therapeutic effect.
However, in view of the current state of cancer treatment, development of a pharmaceutical agent with a greater antitumor effect is required in order to completely inhibit the growth of tumors so as to prolong patient survival.